Subjects
Subjects for the study were recruited from January 2006 to May 2009 through the screening program at Japan Health Promotion Foundation which has been conducting cardiovascular disease and cancer screening throughout major cities in Japan. Subjects were company employees and their family members: 9,881 men and 12,033 women between 17 and 87 years of age. Following Japan’s Personal Information Protection Law, the use of anonymized screening data for research purpose was approved by the board of Japan Health Promotion Foundation. The study was approved by the board of Pacific Rim Disease Prevention Center.
Definition of prediabetes and diabetes mellitus
Following the recommendation from American Diabetes Association [15], persons having diabetes were defined as those having medical history of diabetes and/or taking medication of diabetes and/or whose fasting plasma glucose were equal to or higher than 126 mg/dl and/or whose hemoglobinA1c (HbA1c) were equal to or higher than 6.5 % in NGSP value (48 mmol/mol in IFCC). Persons with the state of prediabetes were defined as those whose fasting plasma glucose was from 100 mg/dl to 125 mg/dl and/or whose HbA1c was from 5.7 % to 6.4 % in NGSP value (39 mmol/mol to 47 mmol/mol in IFCC). Persons defined as “normal” were those without diabetes and prediabetes.
Clinical measurements
Blood was drawn from subjects after a 12 h fast. The following measurements were made: total cholesterol (TC) and triglycerides (TG) by enzymatic assay; high density lipoprotein cholesterol (HDL-C) by modified enzymatic method; glucose by hexokinase glucose-6-phosphate dehydrogenate assay; and glyco-hemoglobin A1c (HbA1c) by latex agglutination.
Following the guideline released by American Heart Association in 2007 [16], persons having hypertension were defined as those having medical history of hypertension and/or taking hypertension drugs and/or whose systolic blood pressure (SBP) was equal to or higher than 140 mmHg and/or whose diastolic blood pressure (DBP) was equal to or higher than 90 mmHg.
Cardio-ankle vascular index
CAVI, a stiffness and arteriosclerosis indicator of thorax, abdomen, common iliac, femoral and tibial arteries, was measured by VaSera VS-1000 manufactured by Fukuda-Denshi Company, LTD (Tokyo, Japan).
As illustrated by Shirai et al. [9], the scale conversion from PWV to CAVI is performed by the following formula:
$$ \mathrm{CAVI}=\mathrm{a}\left\{\left(2\uprho /\Delta \mathrm{P}\right)\ \mathrm{x}\ \ln \left(\mathrm{P}\mathrm{s}/\mathrm{P}\mathrm{d}\right){\mathrm{PWV}}^2\right\} + \mathrm{b} $$
where Ps and Pd are systolic and diastolic blood pressure values, respectively, PWV is the pulse wave velocity between heart and ankle, ∆P is Ps-Pd, ρ is blood density, and a and b are constants. This equation was derived from Bramwell-Hill’s equation [1] and stiffness parameter [10]. Scale conversion constants are determined so as to match CAVI with PWV by Hasegawa’s method [6]. These measurements and calculations are automatically made in VaSera VS-1000.
In the previous study we established the age-sex specific cutoff points of CAVI scores above which were determined to be abnormally high or advanced level of arteriosclerosis [14]. The cutoff points are (mean of CAVI + one standard deviation ) among CVD risk-free subjects: 7.39 for 20-29 years of age, 7.80 for 30-39 years of age, 8.29 for 40-49 years of age, 8.83 for 50-59 years of age, 9.54 for 60-69 years of age, and 10.35 for 70 years of age and over among men; and 7.23 for 20-29 years of age, 7.42 for 30-39 years of age, 7.95 for 40-49 years of age, 8.52 for 50-59 years of age, 8.98 for 60-69 years of age, and 9.46 for 70 years of age and over among women. To apply the logistic regression method for examining the association of prediabetes and diabetes with CAVI scores, CAVI scores of screening participants were converted to a binary variable: 1 for less than cutoff points and 2 for equal or greater than cutoff points or abnormally high CAVI scores.
Questionnaire
A short self-administered questionnaire was filled out by each subject during the screening. It contains questions on medical history and lifestyle factors such as smoking habit and alcohol consumption.
Statistical methods
All statistical analyses were performed gender-specifically. To examine characteristics of study participants by diabetes status, Student’s t-tests and chi-square tests were conducted for detecting significant differences in means and in prevalence, respectively, between persons with normal status and persons with prediabetes and diabetes. Cochran-Armitage test for linear trend was applied to evaluate the dose-dependent association between the degree of glycemic status and the prevalence of abnormally high CAVI scores. Crude, age-adjusted and multivariable-adjusted odds ratios (OR) and the 95 % confidence intervals (CI) of abnormally high CAVI scores according to diabetic status were calculated in logistic regression models, with normal persons who were treated as the reference category. In the age-adjusted model, age was entered as a variable of 10-year interval categories (50-59, 60-69, 70+ vs. <50). The multivariable model was further adjusted for major CVD risk factors including hypertension (yes vs. no), HDL-C (≥40 mg/dl vs. <40 mg/dl for males, ≥50 mg/dl vs. <50 mg/dl for females), triglycerides (150-199 mg/dl, ≥200 mg/dl vs. <150 mg/dl), BMI (20-22.9, 23-24.9, 25-27.9, 28-29.9, 30+ vs. <20), drinking habit (≤4 times/week, ≥5 times/week vs. non-drinkers), and smoking habit (ex-smokers, current smokers vs. non-smokers).
